JPH0460113B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel bisbenzofuran derivatives, more specifically, the general formula () (In the formula, R ¹ is hydrogen or halogen, X is -CO
-, -CH ₂ - or -CHOH-, m and n independently represent an integer of 1 or 2, and OH group and R ¹
The present invention relates to bisbenzofuran derivatives () represented by the group substituted at any position of the 4, 5, 6, or 7 position of the benzofuran ring, alkali salts thereof, and methods for producing them. In the bisbenzofuran derivative ()
Among R ¹ groups, halogens include chlorine, bromine, and iodine. The compound of the present invention itself has antiviral activity and is useful as a medicine, and is also useful as a pharmaceutical intermediate for interferoinducers, antitumor agents, enzyme inhibitors, and the like. Bis(6-hydroxy-2-benzofuranyl) ketone, bis(7-hydroxy-2-benzofuranyl) ketone, bis(5-hydroxy-2-benzofuranyl) ketone,
In the general formula (), such as bis(4-hydroxy-2-benzofuranyl) ketone, bis(4,6-dihydroxy-2-benzofuranyl) ketone, bis(4-chloro-7-hydroxy-2-benzofuranyl) ketone, R Bisbenzofuran derivatives in which ¹ is hydrogen or chlorine, X is -CO-, and m is 1, and alkali salts thereof are preferred. The bisbenzofuran derivative () of the present invention has the general formula () (In the formula, R represents a lower alkyl group, R ¹ ,
m and n have the same meanings as above, and the RO group and R ¹ group are substituted at any position of the 4, 5, 6, or 7 position of the benzofuran ring. It is easily produced by alkylation. The dealkylation reaction is carried out by heating the bisbenzofuran derivative () in an appropriate solvent such as benzene, chlorobenzene, dichlorobenzene, acetic acid, methanol, or ethanol in the presence of an acid catalyst at room temperature or under reflux for several hours. This is preferably carried out. Preferred examples of the acid catalyst used include anhydrous aluminum chloride, anhydrous tin chloride, Lewis acids such as boron trifluoride, mineral acids such as hydrochloric acid and hydrobromic acid, and pyridine hydrochloride. Starting material bisbenzofuran derivative ()
In, the lower alkyl group represented by R is methyl, ethyl, n-propyl, isopropyl,
Examples include straight-chain or branched alkyl groups having 1 to 4 carbon atoms, such as n-butyl or isobutyl, and among these, methyl is particularly preferred. Among those represented by R ¹ , suitable halogens include chlorine, bromine, and iodine.
Note that when the R ¹ group is bromine or iodine, debromination or deiodination reactions may occur depending on the type of acid catalyst, but the products obtained in such cases may not be the same as those of the present invention. It is included in bisbenzofuran derivatives () (the product is a bisbenzofuran derivative () in which R ¹ is hydrogen). Among the bisbenzofuran derivatives () of the present invention, general formula () (In the formula, X ¹ represents -CH ₂ - or -CHOH-, R ¹ , m and n have the same meanings as above, and OH group and R ¹ group are
(substituted at any position of 5, 6 or 7)
The bisbenzofuranylmethane derivative () (X ¹ = -CH ₂ -) or the bisbenzofuranyl methanol derivative () (X ¹ = -CHOH-) represented by the general formula () (In the formula, R, R ¹ , m and n have the same meanings as above, and the RO group and R ¹ group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) The shown bisbenzofuranyl ketone derivative () is dealkylated to obtain the general formula () among the bisbenzofuran derivatives (). (In the formula, R ¹ , m and n have the same meanings as above, and the OH group and R ¹ group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) It can also be obtained by obtaining a bisbenzofuranyl ketone derivative () and then reducing it. That is, when bisbenzofuranyl ketone derivative () is reduced using a reducing agent such as hydrazine hydrate or catalytically reduced using palladium carbon, Raney-nickel catalyst, etc., bisbenzofuranylmethane derivative () (X ¹ = −CH ₂ −), or sodium borohydride, lithium borohydride,
Reduction using a reducing agent such as lithium aluminum hydride provides the bisbenzofuranyl methanol derivative (X ¹ =-CHOH-).
As the solvent in the reduction reaction, water, methanol, diethylene glycol, or a mixed solvent thereof is preferably used. As the reaction temperature, a temperature in the range of 0 to 120°C is appropriately adopted, and as the reaction time, a time in the range of several minutes to several hours is appropriately adopted. Examples of the alkali salts of the bisbenzofuran derivative () of the present invention include inorganic salts such as sodium salts and potassium salts, and these can be prepared in a conventional manner using a suitable solvent, e.g. It can be easily obtained by reacting an aqueous alkaline solution such as sodium hydroxide or potassium hydroxide in a solvent such as methanol or ethanol. All of the bisbenzofuran derivatives () that are the starting materials in the present invention are new compounds, but those in which X is -CO- (bisbenzofuranyl ketone derivatives ()), for example, have the general formula () (In the formula, R, R ¹ , m and n are the same as above)
Salicylaldehyde () and 1,3-
It can be easily obtained by reacting dichloroacetone with a suitable solvent such as dioxane, acetone, water, etc. in the presence of a suitable deoxidizer such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. Among bisbenzofuran derivatives (), those in which X is -CH ₂ - can be obtained by reducing the bisbenzofuranyl ketone derivative with a reducing agent such as hydrazine hydrate or by catalytic reduction using a catalyst such as palladium on carbon or Raney nickel. It can be easily obtained by doing. Among bisbenzofuran derivatives (), those in which X is -CHOH- can be easily obtained by reducing the bisbenzofuranyl ketone derivative with a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, etc. available. Also, R ¹ of bisbenzofuran derivatives ()
For bisbenzofuran derivatives () in which the group is halogen, those in which R ¹ group is hydrogen are treated with a suitable halogen agent, such as chlorine, sulfuryl chloride,
It can also be obtained by halogenation with bromine, N-bromosuccinimide, etc. The bisbenzofuran derivatives () and their alkali salts of the present invention are all new compounds that themselves have excellent antiviral effects and are useful as medicines, as well as interferoinducers, antitumor agents, and enzyme inhibitors. It is also useful as a pharmaceutical intermediate such as. For example, bisbenzofuran derivatives () and their alkali salts can be used to prevent various diseases such as colds, pharyngitis, pool fever, influenza, pneumonia, and other respiratory infections caused by various viruses, as well as cystitis zoster and keratitis. Effective for treatment. Furthermore, basic alkoxy-substituted bisbenzofuran derivatives obtained by reacting bisbenzofuran derivatives () with substituted aminoalkyl halides also exhibit similar pharmacological effects. The compounds of the present invention have lower toxicity than known antiviral agents, such as bis(6-hydroxy-
2-Benzofuranyl) ketone has an LD ₅₀ of 2000 mg/Kg or more (oral administration), 2000 mg/Kg or more (subcutaneous administration), or 800 mg/Kg or more in an acute toxicity test using mice.
Kg or more (intraperitoneal administration). Next, the present invention will be explained with reference to reference examples and examples. Note that parts in the examples are parts by weight unless otherwise specified. Reference example 1 [bis(7-methoxy-2-benzofuranyl)
Production of ketone] 3-methoxysalicylaldehyde 3.4g (0.022
mol) in 15 ml of dioxane, add to this at room temperature,
Add 1 g (0.025 mol) of sodium hydroxide while stirring, gradually heat and react at 75°C for 20 to 30 minutes.
Then 1,3 g of 1,3-dichloroacetone
(0.010 mol) was added little by little and the reaction was further carried out at 80°C for 30 minutes. After cooling the reaction solution, add 200ml of water.
The resulting precipitate was collected by filtration, dried, and then dissolved in ethanol.
Recrystallization from 100ml yielded 1.0g of bis(7-methoxy-2-benzofuranyl)ketone in the form of yellowish brown needles with a melting point of 143-144°C. Elemental analysis value: C ₁₉ H ₁₄ O ₅ Calculated value: C70.80 H4.38 Actual value: C71.09 H4.09 Reference examples 2 to 7 4- instead of 3-methoxysalicylaldehyde
Methoxysalicylaldehyde, 5-methoxysalicylaldehyde, 6-methoxysalicylaldehyde, 3-ethoxysalicylaldehyde, 4-n-
Reference Example 2 Bis(6-methoxy-2-benzofuranyl) ketone Yellowish brown crystals, melting point 191-193℃ Elemental analysis value : As C ₁₉ H ₁₄ O ₅ Calculated value: C70.80 H4.38 Actual value: C70.89 H4.41 Reference example 3 Bis(5-methoxy-2-benzofuranyl) ketone Yellow crystals, melting point 173-174℃ Elemental analysis Value: As C ₁₉ H ₁₄ O ₅ Calculated value: C70.80 H4.38 Actual value: C70.97 H4.50 Reference example 4 Bis(4-methoxy-2-benzofuranyl) ketone Yellowish brown crystals, melting point 181-183℃ Elemental analysis value: C ₁₉ H ₁₄ O ₅ Calculated value: C70.80 H4.38 Actual value: C70.71 H4.28 Reference example 5 Bis(7-ethoxy-2-benzofuranyl) ketone Yellow-brown needle crystals, melting point 135-137℃ Elemental analysis value: _{C21H18O5 Calculated} value: C71.99 _H5.18 Actual value: C71.76 H5.33 Reference example 6 Bis(6-n-butoxy-2-benzofuranyl)ketone Yellow Brown crystals, melting point 121-123℃ Elemental analysis value: C ₂₅ H ₂₆ O ₅ Calculated value: C73.87 H6.45 Actual value: C73.99 H6.20 Reference example 7 Bis(4,6-dimethoxy-2- Benzofuranyl) ketone yellow crystals, melting point 201-203°C Elemental analysis value: C ₂₁ H ₁₈ O ₇ Calculated value: C65.97 H4.74 Actual value: C66.25 H4.91. Reference example 8 [bis(7-ethoxy-2-benzofuranyl)
Production of methane] Bis(7-ethoxy-2-
2.5 g (0.007 mol) of benzofuranyl) ketone, 50 ml of diethylene glycol, and 3.5 g of 80% hydrazine hydrate were mixed and heated at about 110°C for 30 minutes.
Then, when 5.5 g of potassium hydroxide was added, a reaction occurred with the vigorous generation of hydrogen gas. Approximately 120 more
After heating at ℃ for 30 minutes, gas evolution almost ceased. After cooling, the reaction solution was poured into water, a small amount of red precipitate was removed by filtration, and the filtrate was acidified to produce a precipitate. The precipitate was collected by filtration, dried, and then recrystallized from ethanol to obtain 1.0 g of bis(7-ethoxy-2-benzofuranyl)methane in the form of a reddish brown powder with a melting point of 90-92°C. Elemental analysis value: C ₂₁ H ₂₀ O ₄ Calculated value: C74.98 H5.99 Actual value: C74.69 H5.93 Reference example 9 [Bis(7-methoxy-2-benzofuranyl)
Production of methane] Produced in the same manner as in Reference Example 8, except that bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1 was used instead of bis(7-ethoxy-2-benzofuranyl) ketone, with a melting point of 117. Bis(7-methoxy-2-benzofuranyl)methane was obtained as a reddish-brown powder with a temperature of ~119°C. Elemental analysis value: C ₁₉ H ₁₆ O ₄ Calculated value: C74.01 H5.23 Actual value: C73.79 H5.43 Reference example 10 [Bis(7-ethoxy-2-benzofuranyl)
Production of methanol] Bis(7-ethoxy-2-
2.5 g (0.007 mol) of benzofuranyl)ketone was suspended in 50 ml of methanol, and to this was added a solution of 0.6 g of sodium hydroxide in 5 ml of water at room temperature with stirring. While cooling the reaction solution in an ice water bath, add 0.25 g of sodium borohydride while stirring, and add 15 g of sodium borohydride.
After stirring for a minute, the mixture was further stirred at room temperature for 1 hour. After the reaction was completed, methanol was removed, the residue was poured into water, and the precipitate precipitated was collected by filtration and dried to obtain 2.0 g of bis(7-ethoxy-2-benzofuranyl)methanol in the form of a yellowish brown powder with a decomposition point of 97-99°C. Elemental analysis value: C ₂₁ H ₂₀ O ₅ Calculated value: C71.58 H5.72 Actual value: C71.72 H5.87 Reference example 11 [Production of bis(4-chloro-7-methoxy-2-benzofuranyl) ketone ] Bis(7-methoxy-2-
Dissolve 3.2 g (0.01 mol) of benzofuranyl) ketone in 30 ml of chloroform, and while gently refluxing the mixture, dissolve 3.0 g (0.022 mol) of sulfuryl chloride.
was dissolved in 6 ml of chloroform.
It took several minutes to drip. After the dropwise addition, refluxing was continued for another 2 hours. The reaction solution was cooled and the precipitated crystals were collected by filtration to obtain 1.3 g of pale yellow crystalline bis(4-chloro-7-methoxy-2-benzofuranyl)ketone with a melting point of 218-220°C. This product showed positive results in a qualitative halogen reaction, and was confirmed to be the desired compound by measuring infrared absorption spectra and nuclear magnetic resonance absorption spectra. Elemental analysis value: C ₁₉ H ₁₂ O ₅ Cl ₂ Calculated value: C58.33 H3.09 Cl18.12 Actual value: C58.16 H3.31 Cl18.31 Reference example 12 [Bis(4,5-dichloro-7 -methoxy-2
-Production of benzofuranyl)ketone] Instead of 3-methoxysalicylaldehyde, 3-
Melting point 295
Yellow crystalline bis(4,5-dichloro-
7-methoxy-2-benzofuranyl) ketone was obtained. Elemental analysis value: C ₁₉ H ₁₀ O ₅ Cl ₄ Calculated value: C49.60 H2.19 Cl30.82 Actual value: C49.33 H2.47 Cl30.62 Example 1 [Bis(7-hydroxy-2-benzofuranyl ) Production of ketone] Bis(7-methoxy-2-
7.5 g (0.023 mol) of benzofuranyl) ketone and 60 ml of chlorobenzene were mixed, and 9.3 g (0.069 mol) of anhydrous aluminum chloride was added little by little at room temperature while stirring. The reaction solution immediately became a red viscous liquid. Then, the mixture was gradually heated and reacted at 100°C for 1 hour, and a reddish brown precipitate was deposited. After the reaction is complete, the reaction product is poured into water and the precipitate is collected by filtration and dried.
Then, when recrystallized from ethanol, the decomposition point is 268 ~
Yellow crystalline bis(7-hydroxy-2
-Benzofuranyl)ketone 5.7 g were obtained. Elemental analysis value: As C ₁₇ H ₁₀ O ₅・H ₂ O Calculated value: C65.39 H3.89 Actual value: C65.17 H3.94 Elemental analysis value: As C ₁₇ H ₁₀ O ₅ (Dried at 110℃ for 7 hours) ) Calculated value: C69.39 H3.43 Actual value: C69.51 H3.21 Add 3.0 g (0.01 mol) of the above bis(7-hydroxy-2-benzofuranyl) ketone to 150 ml of ethanol.
When heated, add 0.8g of sodium hydroxide to it.
(0.02 mol) dissolved in 20 ml of water was added, and the reaction solution was slightly concentrated and then cooled to form a precipitate. The precipitate was collected by filtration and dried to obtain 3.0 g of disodium salt of bis(7-hydroxy-2-benzofuranyl) ketone in the form of an orange-yellow powder with a melting point of 280° C. or higher. Also, use potassium hydroxide instead of sodium hydroxide.
A reddish-brown powdery bis(7-
2.7 g of dipotassium salt of hydroxy-2-benzofuranyl) ketone was obtained. Example 2 [Production of bis(6-hydroxy-2-benzofuranyl) ketone] Bis(6-methoxy-2-benzofuranyl) ketone obtained in Reference Example 2 was used in place of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(6-hydroxy-2-benzofuranyl)ketone having a decomposition point of 256 to 258°C was obtained in the same manner as in Example 1, except for the following steps. Elemental analysis value: _C17H10O5・₁ / _2H2O Calculated value: C67.55 H3.33 Actual value: C67.36 H3.56 The above bis(6-hydroxy-2 _- benzofuranyl) ketone was used as an example. Processed in the same manner as 1 to obtain a melting point of 280
A disodium salt in the form of a black-red powder with a temperature above ℃ was obtained. Example 3 [Production of bis(5-hydroxy-2-benzofuranyl) ketone] Bis(5-methoxy-2-benzofuranyl) ketone obtained in Reference Example 3 was used in place of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(5-hydroxy-2-benzofuranyl) ketone having a decomposition point of 277 to 278°C was obtained in the same manner as in Example 1, except for the above. Elemental analysis value: _C17H10O5・_H2O Calculated value: C65.39 H3.87 Actual value: C65.39 H3.72 The above bis(5-hydroxy-2 _- benzofuranyl) ketone was used as Example 1 _. Processed similarly to melting point
An orange-red powder disodium salt with a temperature of 280℃ or higher was obtained. Example 4 [Production of bis(4-hydroxy-2-benzofuranyl) ketone] Bis(4-methoxy-2-benzofuranyl) ketone obtained in Reference Example 4 was used in place of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(4-hydroxy-2-benzofuranyl)ketone having a decomposition point of 235 to 237°C was obtained in the same manner as in Example 1, except for the above. Elemental analysis value: _C17H10O5 Calculated value: _{C69.39 H3.43} Actual value: C69.17 H3.52 The bis(4-hydroxy-2-benzofuranyl) ketone was treated in the same manner as in Example 1. melting point 280
A disodium salt in the form of a maroon powder with a temperature above ℃ was obtained. Example 5 [Production of bis(7-hydroxy-2-benzofuranyl) ketone] Bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 5 was used in place of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(7-hydroxy-2-benzofuranyl) ketone having a decomposition point of 268 to 269°C was obtained in the same manner as in Example 1, except for the above. Example 6 [Bis(6-hydroxy-2-benzofuranyl) ketone production] Bis(6-n-butoxy-2-benzofuranyl) ketone obtained in Reference Example 6 was used instead of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(6-hydroxy-2-benzofuranyl)ketone having a decomposition point of 256 to 258°C was obtained in the same manner as in Example 1, except that the following was used. Example 7 [Production of bis(7-hydroxy-2-benzofuranyl)methane] 1.2 g (0.04 mol) of bis(7-methoxy-2-benzofuranyl)methane obtained in Reference Example 9 and 15 ml of chlorobenzene were mixed, and the mixture was heated at room temperature. 1.1 g (0.08 mol) of anhydrous aluminum chloride was added little by little while stirring. Then, the mixture was gradually heated and reacted at 100°C for 1 hour, and a red-black precipitate was deposited. After the reaction, the final reaction product was poured into water to precipitate. After the reaction was completed, the reaction product was poured into water and the precipitate was collected by filtration, dried, and then heated for 20 minutes.
Melting point 154-155 as recrystallized from % aqueous ethanol
ocher flaky bis(7-hydroxy-2
-Benzofuranyl)methane 0.7g was obtained. Elemental analysis value: C ₁₇ H ₁₂ O ₄ Calculated value: C72.85 H4.32 Actual value: C72.56 H4.41 0.1 g of the above bis(7-hydroxy-2-benzofuranyl)methane was added in the same manner as in Example 1. Processed to produce disodium salt in the form of an ocher powder with a melting point of 280℃ or higher
I got 0.07g. Example 8 [Production of bis(7-hydroxy-2-benzofuranyl)methane] Bis(7-ethoxy-2-benzofuranyl)methane obtained in Reference Example 8 was used instead of bis(7-methoxy-2-benzofuranyl)methane. Ocher scale-like bis(7-hydroxy-2-benzofuranyl)methane having a melting point of 154 to 155°C was obtained in the same manner as in Example 7, except for the following steps. Example 9 [Production of bis(7-hydroxy-2-benzofuranyl)methanol] 1.4 g (0.004 mol) of bis(7-ethoxy-2-benzofuranyl)methanol obtained in Reference Example 10 and 15 ml of chlorobenzene were mixed, and the mixture was heated to room temperature. 1.6 g (0.012 mol) of anhydrous aluminum chloride was added little by little while stirring. Then, when the mixture was gradually heated and reacted at 100°C for 30 minutes, a reddish-black precipitate was deposited. After the completion of the reaction, the reactant was poured into water and the aqueous layer was removed by decantation, the remaining precipitate was collected, and this was recrystallized from 20% water-containing methanol to produce bis(7-hydroxy-2-benzofuranyl) as a grayish-white powder with a melting point of 270°C or higher. ) 0.5g of methanol was obtained. Elemental analysis value: _C17H12O5 Calculated value: C68.92 _H4.08 Actual value: C68.93 H3.87 Example 10 [Production of bis(7-hydroxy-2 _- benzofuranyl) ketone] Reference example 5 1.2 g (0.0033 mol) of the resulting bis(7-ethoxy-2-benzofuranyl) ketone was dissolved in 3.5 g of glacial acetic acid, and 1.4 ml (0.008 mol) of 48% hydrobromic acid was gradually added dropwise to this under stirring and reflux. did. After the dropwise addition was completed, the mixture was further stirred and reacted under reflux for 1 hour.
After the reaction is completed, the reaction solution is extracted with a dilute alkaline aqueous solution.
The alkaline layer was acidified with dilute hydrochloric acid, the resulting precipitate was filtered, dried, and then recrystallized from ethanol to obtain 0.45 g of yellow crystalline bis(6-hydroxy-2-benzofuranyl) ketone with a decomposition point of 268-269°C. . Example 11 [Production of bis(7-hydroxy-2-benzofuranyl)methane] Bis(7-methoxy-2-benzofuranyl)methane obtained in Reference Example 8 was used instead of bis(7-ethoxy-2-benzofuranyl)ketone. Ocher scale-like bis(7-hydroxy-2-benzofuranyl)methane having a melting point of 154 to 155°C was obtained in the same manner as in Example 10, except for the above. Example 12 [Production of bis(4,6-dihydroxy-2-benzofuranyl)ketone] Bis(4,6-dimethoxy-2-benzofuranyl) obtained in Reference Example 7
- 2.0 g (0.005 mol) of benzofuranyl)ketone and 15 ml of chlorobenzene are mixed, and 3.3 g (0.025 mol) of anhydrous aluminum chloride is added to the mixture at room temperature with stirring.
was added little by little. The reaction solution immediately turned into a red viscous liquid. Then, the mixture was gradually heated and reacted at 100°C for 1 hour, and a red-black precipitate was deposited. After the reaction, the reaction product was poured into water, the precipitate was filtered and dried, and then recrystallized from 20% aqueous ethanol to obtain orange-red crystalline bis(4,6-hydroxy-2-benzofuranyl)ketone with a melting point of 280 or higher. I gained 1.4g. Elemental analysis value: C ₁₇ H ₁₀ O ₇ Calculated value: C62.58 H3.09 Actual value: C62.36 H2.88 0.5 g of the above bis(4,6-dihydroxy-2-benzofuranyl) ketone was added to Example 1. A similar treatment yielded 0.4 g of tetrasodium salt in the form of black-red powder with a melting point of 280°C or higher. Example 13 [Production of bis(7-hydroxy-2-benzofuranyl)methane] 0.5 g (0.0016 mol) of bis(7-hydroxy-2-benzofuranyl) ketone obtained in Example 1, 80%
Mix 0.3 g of hydrazine hydrate and 6 ml of diethylene glycol and heat at 110-120°C with stirring.
Heat for 30 minutes, then add 1.1g of alkali hydroxide.
(0.02 mol) was added. At this time, a large amount of nitrogen gas was generated. The mixture was further heated at around 120°C for about 1 hour until almost no nitrogen gas was generated. After cooling, the reaction solution was poured into water for decomposition, and then acidified with dilute hydrochloric acid to form a precipitate. The precipitate was collected by filtration, dried, and then recrystallized from 20% aqueous ethanol to obtain ocher flaky bis(7-hydroxy-2-benzofuranyl)methane with a melting point of 154-155°C.
I gained 0.2g. Example 14 [Production of bis(7-hydroxy-2-benzofuranyl)methanol] 1.2 g (0.004 mol) of bis(7-hydroxy-2-benzofuranyl) ketone obtained in Example 1 was suspended in 20 ml of methanol, and Sodium hydroxide
When a solution of 0.32 g (0.008 mol) dissolved in 20 ml of water was added, the mixture immediately turned red and after most of the raw material had dissolved, a small amount of precipitate was deposited again. While cooling the reaction solution to 5° C. in an ice-water bath, 0.14 g (0.04 mol) of sodium borohydride was added, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for about 2 hours. At the end of the reaction, most of the precipitate disappeared, turning into a reddish-yellow solution. After the reaction was completed, the reaction solution was poured into water and acidified with dilute hydrochloric acid. The precipitate was collected by filtration, dried, and recrystallized from 20% water-containing methanol to obtain bis(7-hydroxy-2- 0.6 g of benzofuranyl) methanol was obtained. Example 15 [Bis(4--chloro-7-hydroxy-2-
Production of benzofuranyl) ketone] 4 g (0.01 mol) of bis(4-chloro-7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 11 was dissolved in 50 ml of chlorobenzene, and 4 g of anhydrous aluminum chloride ( 0.03 mol) was added and heated at 75-80°C for 30 minutes. After the reaction was completed, the reactant was cooled and poured into ice water for decomposition, and the precipitate precipitated was collected by filtration, dried, and then recrystallized from ethanol to obtain orange-yellow crystalline bis(4-chloro- 3 g of 7-hydroxy-2-benzofuranyl)ketone was obtained. Elemental analysis value: _C17H8O5Cl2 Calculated value: C56.23 _{H2.22 Cl19.52} Actual value: C56.06 H2.42 Cl19.21 The above bis(4 _- chloro-7-hydroxy-2-
1.0g of benzofuranyl)ketone was treated in the same manner as in Example 1 to obtain 0.9g of disodium in the form of a maroon powder with a melting point of 280°C or higher. Example 16 [Bis(4,5-dichloro-7-hydroxy-
Production of 2-benzofuranyl) ketone] Same procedure except that bis(4,5-dichloro-7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 12 was used instead of bis(7-methoxy-2-benzofuranyl) ketone. Melting point 295 as in Example 1
Bis(4,5-dichloro-7-hydroxy-2-benzofuranyl)ketone was obtained as orange-yellow needle-shaped crystals with a temperature of 0.degree. C. or higher. Elemental analysis value: C ₁₇ H ₆ O ₅ Cl ₄ Calculated value: C47.26 H1.40 CL32.82 Actual value: C47.47 H1.43 Cl32.59 Example 17 [Antiviral test in chicken fetal fibroblasts] ] Fetuses from embryonated chicken eggs aged 10 to 11 days were tissue cultured in a conventional manner, and solutions of various concentrations of bisbenzofuran compounds dissolved in methanol or water and culture medium were added to primary chicken fetal fibroblasts cultured for 20 to 24 hours. The challenge was made with influenza A-PR8 diluted with (last challenge m.o.i = 0.1 to 0.2). The cells were then incubated at 37°C, and after 48 hours, the amount of virus in the culture medium was determined by the HA (hemagglutination reaction) test, and the amount of virus in the cells was determined by heme adsorption. The minimum concentration at which virus activity was expressed was determined. The cytotoxicity of the test compound was examined in the same experimental system as above without virus challenge, and the effectiveness coefficient was determined from the following formula. Effectiveness coefficient=minimum concentration for cytotoxicity/minimum concentration for antiviral activity For comparison, the same test as above was conducted on Amantadine, which has been conventionally used as an antiviral agent. These results are shown in Table 1.

【table】

[Table] Example 18 [Effect on death of virus-infected mice] The disodium salt of bis(6-hydroxy-2-benzofuranyl) ketone, which showed the strongest antiviral effect in Example 17, had an effect on death of influenza virus-infected mice. We investigated the effects on 90 mice weighing 25 g were divided into a control group (30 mice), a test group () (30 mice), and a test group ().
The mice in all groups were intranasally infected with a lethal dose ( _3ILD50 ) of influenza virus A-PR8. 10% for test group () and test group ()
A disodium salt of bis(6-hydroxy-2-benzofuranyl) ketone suspended in an aqueous solution of gum arabic was administered intraperitoneally at a dose of 50 mg/Kg/day. The control drug group also included Tilorone.
was orally administered at a dose of 250 mg/Kg/day. The administration period is for the test group () to prevent viral infection.
From 48 hours before the infection to the 3rd day after infection, from the 4th day to the 9th day after infection for the test group (), and once every 24 hours after virus infection for the control drug group (). I went only. whereas the control group had 10
% aqueous gum arabic solution alone was administered intraperitoneally.
When the four groups were observed for 20 days after virus infection, the control group showed a 50% reduction between days 8 and 13.
of mice died, while 30% in the test group ();
In the test group () only 10% of the mice died. In addition, the mortality rate of mice in the control drug group () administered with Tyrolone, which is known to be a powerful interferon inducer, was 20%.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is hydrogen or halogen, X is -CO
-, -CH ₂ - or -CHOH-, m and n independently represent an integer of 1 or 2, and OH group and R ¹
Bisbenzofuran derivatives and alkali salts thereof, in which the group is substituted at any position of the 4, 5, 6, or 7 position of the benzofuran ring. 2 In the general formula (), R ¹ is hydrogen or chlorine,
Claim 1 in which X is -CO- and m is 1
Bisbenzofuran derivatives and their alkali salts as described in . 3. The bisbenzofuran derivative and its alkali salt according to claim 2, which is bis(6-hydroxy-2-benzofuranyl)ketone. 4. The bisbenzofuran derivative and its alkali salt according to claim 2, which is bis(7-hydroxy-2-benzofuranyl)ketone. 5. The bisbenzofuran derivative and its alkali salt according to claim 2, which is bis(5-hydroxy-2-benzofuranyl)ketone. 6. The bisbenzofuran derivative and its alkali salt according to claim 2, which is bis(4-hydroxy-2-benzofuranyl)ketone. 7. The bisbenzofuran derivative and its alkali salt according to claim 2, which is bis(4,6-dihydroxy-2-benzofuranyl)ketone. 8. Claim 2, which is bis(4-chloro-7-hydroxy-2-benzofuranyl)ketone
Bisbenzofuran derivatives and their alkali salts as described in . 9 General formula (In the formula, R is a lower alkyl group, R ¹ is hydrogen or halogen, X is -CO-, -CH ₂ - or -
CHOH-, m and n independently represent an integer of 1 or 2, and the RO group and R ¹ group are substituted at any position of the 4, 5, 6, or 7 position of the benzofuran ring). General formula characterized by dealkylation of derivatives (In the formula, R ¹ , X, m and n have the same meanings as above, and the OH group and R ¹ group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring). A method for producing the bisbenzofuran derivative and its alkali salt shown. 10. The manufacturing method according to claim 9, wherein R in the general formula () is a methyl group. 11 General formula (In the formula, R is a lower alkyl group, R ¹ is hydrogen or halogen, m and n independently represent an integer of 1 or 2, and the RO group and R ¹ group are at the 4, 5, 6, or 7 position of the benzofuran ring. The bisbenzofuranyl ketone derivative represented by (substituted at any position) is dealkylated to form the general formula (In the formula, R ¹ , m and n have the same meanings as above, and the OH group and R ¹ group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) General formula characterized by obtaining a bisbenzofuranyl ketone derivative and then reducing this derivative (In the formula, R ¹ , m and n have the same meanings as above, X ¹ represents -CH ₂ - or -CHOH-, and the OH group and R ¹ group are 4 of the benzofuran ring,
(substituted at any position of 5, 6 or 7)
A method for producing a bisbenzofuranylmethane derivative or a bisbenzofuranylmethanol derivative and an alkali salt thereof. 12. The production method according to claim 11, wherein R in the general formula () is a methyl group.